DESCRIPTION (adapted from the application) The intestinal epithelium is a major target of graft-versus-host disease (GVHD). Because the intestinal epithelium serves both as an absorptive organ for numerous nutrients and a barrier toward harmful pathogens in the intestinal lumen, injury to the intestinal epithelium alone in GVHD can result in severe morbidity and mortality. GVHD is mediated primarily by donor T cells, which recognize and destroy host cells. Our present understanding of GVHD, however, has been based on studies on donor T cells found in the periphery. Whether these findings are relevant to the mechanism of intestinal epithelial injury in GVHD is not known. Thus, to further understand the mechanism of intestinal epithelial injury in GVHD, we propose to study the donor T cells, which specifically infiltrate the intestinal epithelium during GVHD (Infiltrating Intestinal Intraepithelial Lymphocytes or Infiltrating IEL). Our proposal is based on the hypothesis that intestinal epithelial injury in GVHD is primarily mediated by these Infiltrating IEL which infiltrate the host intestinal epithelium and subsequently induce the apoptotic death of host intestinal epithelial cells (IEC). The questions that emerge from our hypothesis form the basis of our specific aims. Aim 1) What are the mechanisms by which Infiltrating IEL induce intestinal epithelial injury in GVHD? Previous studies have demonstrated that Infiltrating IEL can induce IEC apoptosis through Fas-mediated cytotoxicity. Here we will address whether other mechanisms are also involved. Aim 2) Are Infiltrating IEL necessary for intestinal epithelial apoptosis seen in GVHD? Here, we will address whether the infiltration of donor T cells into the intestinal epithelium is required for the IEC apoptosis seen in GVHD. Aim 3) What is the significance of IEC apoptosis induced by Infiltrating IEL? Here, we will address whether infiltrating IEL can impair well-described IEC function such as disaccharidase activity and intestinal permeability.